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1.
EClinicalMedicine ; 49: 101483, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35747182

ABSTRACT

Background: Ebola virus disease (EVD) outbreaks in West Africa (2013-2016) and the Democratic Republic of Congo (2018-2020) have resulted in thousands of EVD survivors who remain at-risk for survivor sequelae. While EVD survivorship has been broadly reported in adult populations, pediatric EVD survivors are under-represented. In this cross-sectional study, we investigated the prevalence of eye disease, health-related quality-of-life, vision-related quality-of-life, and the burden of mental illness among pediatric EVD survivors in Sierra Leone. Methods: Twenty-three pediatric EVD survivors and 58 EVD close contacts were enrolled. Participants underwent a comprehensive ophthalmic examination and completed the following surveys: Pediatric Quality of Life Inventory Version 4.0, Effect of Youngsters Eyesight on Quality-of-Life, and the Revised Child Anxiety and Depression Scale. Findings: A higher prevalence of uveitis was observed in EVD survivor eyes (10·8%) cohort compared to close contacts eyes (1·7%, p=0·03). Overall, 47·8% of EVD survivor eyes and 31·9% of close contact eyes presented with an eye disease at the time of our study (p=0·25). Individuals diagnosed with an ocular complication had poorer vision-related quality-of-life (p=0·02). Interpretation: Both health related quality-of-life and vision-related quality-of-life were poor among EVD survivors and close contacts. The high prevalence of eye disease associated with reduced vision health, suggests that cross-disciplinary approaches are needed to address the unmet needs of EVD survivors. Funding: National Institutes of Health R01 EY029594, K23 EY030158; National Eye Institute; Research to Prevent Blindness (Emory Eye Center); Marcus Foundation Combating Childhood Illness; Emory Global Health Institute; Stanley M. Truhlsen Family Foundation.

2.
Clin Exp Immunol ; 204(1): 134-143, 2021 04.
Article in English | MEDLINE | ID: mdl-33423291

ABSTRACT

Interferon regulatory factor 5 (IRF5) is a master regulator of macrophage phenotype and a key transcription factor involved in expression of proinflammatory cytokine responses to microbial and viral infection. Here, we show that IRF5 controls cellular and metabolic responses. By integrating ChIP sequencing (ChIP-Seq) and assay for transposase-accessible chromatin using sequencing (ATAC)-seq data sets, we found that IRF5 directly regulates metabolic genes such as hexokinase-2 (Hk2). The interaction of IRF5 and metabolic genes had a functional consequence, as Irf5-/- airway macrophages but not bone marrow-derived macrophages (BMDMs) were characterized by a quiescent metabolic phenotype at baseline and had reduced ability to utilize oxidative phosphorylation after Toll-like receptor (TLR)-3 activation, in comparison to controls, ex vivo. In a murine model of influenza infection, IRF5 deficiency had no effect on viral load in comparison to wild-type controls but controlled metabolic responses to viral infection, as IRF5 deficiency led to reduced expression of Sirt6 and Hk2. Together, our data indicate that IRF5 is a key component of AM metabolic responses following influenza infection and TLR-3 activation.


Subject(s)
Energy Metabolism/immunology , Gene Expression Regulation/immunology , Interferon Regulatory Factors/immunology , Macrophages/immunology , Respiratory System/cytology , Animals , Cells, Cultured , Chromatin Immunoprecipitation Sequencing/methods , Energy Metabolism/genetics , Female , Hexokinase/genetics , Hexokinase/immunology , Hexokinase/metabolism , Humans , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/metabolism , Macrophages/metabolism , Mice, Inbred C57BL , Mice, Knockout , Sirtuins/genetics , Sirtuins/immunology , Sirtuins/metabolism , Toll-Like Receptor 3/genetics , Toll-Like Receptor 3/immunology , Toll-Like Receptor 3/metabolism
3.
Clin Exp Allergy ; 48(10): 1275-1285, 2018 10.
Article in English | MEDLINE | ID: mdl-29900603

ABSTRACT

Whilst severe asthma has classically been categorized as a predominantly Th2-driven pathology, there has in recent years been a paradigm shift with the realization that it is a heterogeneous disease that may manifest with quite disparate underlying inflammatory and remodelling profiles. A subset of asthmatics, particularly those with a severe, corticosteroid refractory disease, present with a prominent neutrophilic component. Given the potential of neutrophils to impart extensive tissue damage and promote inflammation, it has been anticipated that these cells are closely implicated in the underlying pathophysiology of severe asthma. However, uncertainty persists as to why the neutrophil is present in the asthmatic lung and what precisely it is doing there, with evidence supporting its role as a protagonist of pathology being primarily circumstantial. Furthermore, our view of the neutrophil as a primitive, indiscriminate killer has evolved with the realization that neutrophils can exhibit a marked anti-inflammatory, pro-resolving and wound healing capacity. We suggest that the neutrophil likely exhibits pleiotropic and potentially conflicting roles in defining asthma pathophysiology-some almost certainly detrimental and some potentially beneficial-with context, timing and location all critical confounders. Accordingly, indiscriminate blockade of neutrophils with a broad sword approach is unlikely to be the answer, but rather we should first seek to understand their complex and multifaceted roles in the disease state and then target them with the same subtleties and specificity that they themselves exhibit.


Subject(s)
Asthma/etiology , Disease Susceptibility , Neutrophils/immunology , Animals , Asthma/metabolism , Asthma/pathology , Humans , Immunomodulation , Neutrophil Infiltration/immunology , Neutrophils/metabolism , Neutrophils/pathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
4.
Mucosal Immunol ; 11(2): 523-535, 2018 03.
Article in English | MEDLINE | ID: mdl-29067998

ABSTRACT

Mucosal surfaces are under constant bombardment from potentially antigenic particles and so must maintain a balance between homeostasis and inappropriate immune activation and consequent pathology. Epithelial cells have a vital role orchestrating pulmonary homeostasis and defense against pathogens. TGF-ß regulates an array of immune responses-both inflammatory and regulatory-however, its function is highly location- and context-dependent. We demonstrate that epithelial-derived TGF-ß acts as a pro-viral factor suppressing early immune responses during influenza A infection. Mice specifically lacking bronchial epithelial TGF-ß1 (epTGFßKO) displayed marked protection from influenza-induced weight loss, airway inflammation, and pathology. However, protection from influenza-induced pathology was not associated with a heightened lymphocytic immune response. In contrast, the kinetics of interferon beta (IFNß) release into the airways was significantly enhanced in epTGFßKO mice compared with control mice, with elevated IFNß on day 1 in epTGFßKO compared with control mice. This induced a heighted antiviral state resulting in impaired viral replication in epTGFßKO mice. Thus, epithelial-derived TGF-ß acts to suppress early IFNß responses leading to increased viral burden and pathology. This study demonstrates the importance of the local epithelial microenvironmental niche in shaping initial immune responses to viral infection and controlling host disease.


Subject(s)
Influenza A virus/physiology , Influenza, Human/immunology , Lung/physiology , Orthomyxoviridae Infections/immunology , Respiratory Mucosa/physiology , Transforming Growth Factor beta1/metabolism , Animals , Cells, Cultured , Humans , Immunity, Mucosal , Interferon-beta/metabolism , Lung/virology , Mice , Mice, Inbred C57BL , Mice, Knockout , Respiratory Mucosa/virology , Transforming Growth Factor beta1/genetics , Virus Replication
5.
Mucosal Immunol ; 10(4): 1021-1030, 2017 07.
Article in English | MEDLINE | ID: mdl-27966555

ABSTRACT

Triggering receptor expressed on myeloid cells-1 (TREM-1) is expressed on neutrophils and monocyte/macrophages and amplifies Toll-like receptor-mediated inflammation during infection. TREM-1 also exists in an antagonistic soluble form (sTREM-1) that has been used as a peripheral biomarker in sepsis, though the mechanisms of its release are not entirely clear. The requirement of TREM-1 in single microbial infections is controversial, with some studies showing a protective role and others a contribution to immunopathology. Furthermore, the role of membrane-bound and sTREM-1 in polygenic infections is currently unknown. In a mouse co-infection model where preceding viral infection greatly enhances bacteria co-infection, we now determine a mechanisms for the striking increase in sTREM-1 and the loss of TREM-1 on surface of neutrophils. We identified a matrix metalloproteinase (MMP)-9 cleavage site in TREM-1 and that the increase of MMP-9 in bronchoalveolar lavage fluid mirrors sTREM-1 release. In vitro studies with neutrophils and MMP-9 and the reduction of sTREM-1 in vivo after MMP-9 inhibition verifies that this enzyme cleaves TREM-1. Intriguingly, MMP-9 inhibition significantly reduces bacterial load and ensuing immunopathology in a co-infection model. This highlights MMP-9 inhibition as a potential therapeutic via blocking cleavage of TREM-1.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Influenza A Virus, H1N1 Subtype/immunology , Matrix Metalloproteinase 9/metabolism , Membrane Proteins/metabolism , Neutrophils/immunology , Orthomyxoviridae Infections/metabolism , Phenylpropionates/therapeutic use , Pneumococcal Infections/metabolism , Streptococcus pneumoniae/physiology , Triggering Receptor Expressed on Myeloid Cells-1/metabolism , Administration, Intranasal , Animals , Bacterial Load/drug effects , Cells, Cultured , Coinfection , Disease Models, Animal , Female , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/drug therapy , Pneumococcal Infections/drug therapy , Protein Domains , Proteolysis/drug effects
6.
Mucosal Immunol ; 10(3): 716-726, 2017 05.
Article in English | MEDLINE | ID: mdl-27759022

ABSTRACT

Interferon regulatory factor 5 (IRF5) is a key transcription factor involved in the control of the expression of proinflammatory cytokine and responses to infection, but its role in regulating pulmonary immune responses to allergen is unknown. We used genetic ablation, adenoviral vector-driven overexpression, and adoptive transfer approaches to interrogate the role of IRF5 in pulmonary immunity and during challenge with the aeroallergen, house dust mite. Global IRF5 deficiency resulted in impaired lung function and extracellular matrix (ECM) deposition. IRF5 was also essential for effective responses to inhaled allergen, controlling airway hyperresponsiveness, mucus secretion, and eosinophilic inflammation. Adoptive transfer of IRF5-deficient alveolar macrophages into the wild-type pulmonary milieu was sufficient to drive airway hyperreactivity, at baseline or following antigen challenge. These data identify IRF5-expressing macrophages as a key component of the immune defense of the airways. Manipulation of IRF5 activity in the lung could therefore be a viable strategy for the redirection of pulmonary immune responses and, thus, the treatment of lung disorders.


Subject(s)
Eosinophils/immunology , Hypersensitivity/immunology , Interferon Regulatory Factors/metabolism , Lung/physiology , Macrophages, Alveolar/immunology , Adoptive Transfer , Animals , Antigens, Dermatophagoides/immunology , Cell Movement , Cells, Cultured , Extracellular Matrix/metabolism , Female , Interferon Regulatory Factors/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Mucus/metabolism , Pyroglyphidae/immunology
7.
Allergy ; 70(1): 80-9, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25331546

ABSTRACT

BACKGROUND: Alveolar macrophages are sentinels of the pulmonary mucosa and central to maintaining immunological homeostasis. However, their role in governing the response to allergen is not fully understood. Inappropriate responses to the inhaled environment manifest as asthma. METHODS: We utilized a mechanistic IL-13-driven model and a house dust mite allergen mucosal sensitization model of allergic airway disease to investigate the role of alveolar macrophages in regulating pulmonary inflammation. RESULTS: IL-13-dependent eosinophilic and Th2 inflammation was enhanced in mice depleted of alveolar macrophages using clodronate liposomes. Similarly, depletion of alveolar macrophages during house dust mite sensitization or established disease resulted in augmented Th2 immunity and increased allergen-specific IgG1 and IgE. Clodronate treatment also delayed the resolution of tissue inflammation following cessation of allergen challenge. Strikingly, tissue interstitial macrophages were elevated in alveolar macrophage-deficient mice identifying a new homeostatic relationship between different macrophage subtypes. A novel role for the macrophage-derived immunoregulatory cytokine IL-27 was identified in modulating Th2 inflammation following mucosal allergen exposure. CONCLUSIONS: In summary, alveolar macrophages are critical regulators of Th2 immunity and their dysregulation promotes an inflammatory environment with exacerbation of allergen-induced airway pathology. Manipulating IL-27 may provide a novel therapeutic strategy for the treatment of asthma.


Subject(s)
Allergens/immunology , Homeostasis , Lung/immunology , Macrophages, Alveolar/immunology , Animals , Antigens, Dermatophagoides/immunology , Asthma/immunology , Asthma/metabolism , Asthma/pathology , Disease Models, Animal , Disease Progression , Female , Interleukin-13/metabolism , Interleukin-13/pharmacology , Interleukin-27/metabolism , Leukocytes/immunology , Leukocytes/metabolism , Lung/metabolism , Lung/pathology , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/metabolism , Mice , Respiratory Mucosa/immunology , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , Th2 Cells/immunology , Th2 Cells/metabolism
8.
Clin Exp Allergy ; 44(11): 1386-98, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25146585

ABSTRACT

BACKGROUND: γδT cells play a crucial immunoregulatory role in the lung, maintaining normal airway tone and preventing hyperresponsiveness to innocuous allergen. During acute inflammatory episodes, γδT cells promote resolution of acute inflammation. However, their contribution to inflammation-associated airway remodelling remains unexplored. Here we investigate the effects of γδT cell blockade on established allergic airway inflammation and development of remodelling. METHODS: Sensitised mice were exposed to prolonged ovalbumin challenge or continuous house-dust mite exposure to induce chronic inflammation and remodelling. Functional blocking anti-TCRδ antibody was administered therapeutically, and parameters of airway inflammation and remodelling were examined. RESULTS: Therapeutic blockade of γδT cells prevented the typical resolution of acute airway inflammation characterised by elevated eosinophil and Th2 cell numbers. Moreover, the lung displayed exacerbated airway remodelling, typified by excess peribronchiolar collagen deposition. CONCLUSIONS: These results demonstrate a unique role for γδT cells in constraining allergen-induced airway remodelling. Manipulating the γδT cell compartment may therefore contribute to strategies to prevent and treat remodelling.


Subject(s)
Airway Remodeling , Inflammation/immunology , Inflammation/pathology , Respiratory Tract Diseases/immunology , Respiratory Tract Diseases/pathology , T-Lymphocyte Subsets/immunology , Animals , Chronic Disease , Disease Models, Animal , Eosinophils/immunology , Female , Inflammation/metabolism , Mice , Ovalbumin/adverse effects , Ovalbumin/immunology , Proliferating Cell Nuclear Antigen/immunology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Respiratory Tract Diseases/metabolism , T-Lymphocyte Subsets/metabolism , Th2 Cells/immunology
9.
Allergy ; 69(10): 1380-9, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24943330

ABSTRACT

BACKGROUND: Associations between vitamin D status and childhood asthma are increasingly reported, but direct causation and mechanisms underlying an effect remain unknown. We investigated the effect of early-life vitamin D deficiency on the development of murine neonatal allergic airways disease (AAD). METHODS: In utero and early-life vitamin D deficiency was achieved using a vitamin D-deficient diet for female mice during the third trimester of pregnancy and lactation. Offspring were weaned onto a vitamin D-deficient or vitamin D-replete diet, and exposure to intranasal house dust mite (HDM) or saline was commenced from day 3 of life for up to 6 weeks, when airway hyper-responsiveness (AHR), airway inflammation and remodelling were assessed. RESULTS: Neonatal mice that had in utero and early-life vitamin D deficiency had significantly increased pulmonary CD3(+) CD4(+) T1ST2(+) cells and reduced CD4(+) IL-10(+) cells. This effect was enhanced following HDM exposure. AHR in HDM-exposed mice was unaffected by vitamin D status. Introduction of vitamin D into the diet at weaning resulted in a significant reduction in serum IgE levels, reduced pulmonary eosinophilia and peri-bronchiolar collagen deposition. CONCLUSION: Peri-natal vitamin D deficiency alone has immunomodulatory effects including Th2 skewing and reduced IL-10-secreting T regulatory cells, exaggerated with additional allergen exposure. Vitamin D deficiency in early life does not affect AHR, but contributes to disease severity with worse eosinophilic inflammation and airway remodelling. Importantly, supplementation with vitamin D improves both of these pathological abnormalities.


Subject(s)
Asthma/immunology , Hypersensitivity/immunology , Pulmonary Eosinophilia/immunology , Th2 Cells/immunology , Vitamin D Deficiency/immunology , Airway Remodeling , Animals , Animals, Newborn , Bronchial Hyperreactivity/immunology , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Lung/immunology , Mice , Mice, Inbred BALB C
10.
Mucosal Immunol ; 7(2): 379-90, 2014 Mar.
Article in English | MEDLINE | ID: mdl-23945544

ABSTRACT

In the present study, we show therapeutic amelioration of established ovalbumin (OVA)-induced allergic airway disease following house dust mite (HDM) peptide therapy. Mice were sensitized and challenged with OVA and HDM protein extract (Dermatophagoides species) to induce dual allergen sensitization and allergic airway disease. Treatment of allergic mice with peptides derived from the major allergen Der p 1 suppressed OVA-induced airway hyperresponsiveness, tissue eosinophilia, and goblet cell hyperplasia upon rechallenge with allergen. Peptide treatment also suppressed OVA-specific T-cell proliferation. Resolution of airway pathophysiology was associated with a reduction in recruitment, proliferation, and effector function of T(H)2 cells and decreased interleukin (IL)-17⁺ T cells. Furthermore, peptide immunotherapy induced the regulatory cytokine IL-10 and increased the proportion of Fox p3⁺ cells among those expressing IL-10. Tolerance to OVA was not associated with increased IL-35. In conclusion, our results provide in vivo evidence for the creation of a tolerogenic environment following HDM peptide immunotherapy, leading to the therapeutic amelioration of established OVA-induced allergic airway disease.


Subject(s)
Allergens/immunology , Antigens, Dermatophagoides/immunology , Arthropod Proteins/immunology , Cysteine Endopeptidases/immunology , Interleukins/biosynthesis , Ovalbumin/adverse effects , Respiratory Hypersensitivity/immunology , Respiratory Hypersensitivity/metabolism , Animals , Antigens, Dermatophagoides/administration & dosage , Arthropod Proteins/administration & dosage , Cysteine Endopeptidases/administration & dosage , Desensitization, Immunologic , Disease Models, Animal , Epitopes, T-Lymphocyte/immunology , Female , Forkhead Transcription Factors/metabolism , Interleukin-10/metabolism , Interleukin-17/metabolism , Interleukin-5/biosynthesis , Lymphocyte Activation/immunology , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Mice , Peptide Fragments/administration & dosage , Peptide Fragments/immunology , Pneumonia/immunology , Pneumonia/metabolism , Pneumonia/pathology , Respiratory Hypersensitivity/therapy
11.
Allergy ; 68(12): 1579-88, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24117726

ABSTRACT

BACKGROUND: The current paradigm describing asthma pathogenesis recognizes the central role of abnormal epithelial function in the generation and maintenance of the disease. However, the mechanisms responsible for the initiation of airway remodeling, which contributes to decreased lung function, remain elusive. Therefore, we aimed to determine the role of altered pulmonary gene expression in disease inception and identify proremodeling mediators. METHODS: Using an adenoviral vector, we generated mice overexpressing smad2, a TGF-ß and activin A signaling molecule, in the lung. Animals were exposed to intranasal ovalbumin (OVA) without systemic sensitization. RESULTS: Control mice exposed to inhaled OVA showed no evidence of pulmonary inflammation, indices of remodeling, or airway hyper-reactivity. In contrast, local smad2 overexpression provoked airway hyper-reactivity in OVA-treated mice, concomitant with increased airway smooth muscle mass and peribronchial collagen deposition. Pulmonary eosinophilic inflammation was not evident, and there was no change in serum IgE or IgG1 levels. The profound remodeling changes were not mediated by classical pro-inflammatory Th2 cytokines. However, uric acid and interleukin-1ß levels in the lung were increased. Epithelial-derived endothelin-1 and fibroblast growth factor were also augmented in smad2-expressing mice. Blocking endothelin-1 prevented these phenotypic changes. CONCLUSIONS: Innate epithelial-derived mediators are sufficient to drive airway hyper-reactivity and remodeling in response to environmental insults in the absence of overt Th2-type inflammation in a model of noneosinophilic, noninflammed types of asthma. Targeting potential asthma therapies to epithelial cell function and modulation of locally released mediators may represent an effective avenue for therapeutic design.


Subject(s)
Airway Remodeling , Asthma/immunology , Asthma/pathology , Endothelin-1/immunology , Airway Remodeling/genetics , Airway Remodeling/immunology , Animals , Asthma/genetics , Bronchial Hyperreactivity/immunology , Disease Models, Animal , Endothelin-1/genetics , Female , Gene Expression , Inflammation Mediators/blood , Inflammation Mediators/metabolism , Mice , Mice, Transgenic , Muscle, Smooth/immunology , Muscle, Smooth/metabolism , Muscle, Smooth/pathology , Ovalbumin/immunology , Respiratory Mucosa/immunology , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , Smad2 Protein/genetics
12.
Mucosal Immunol ; 6(2): 335-46, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22892938

ABSTRACT

The role of T-helper type 17 (Th17) responses in airway remodeling in asthma is currently unknown. We demonstrate that both parenteral and mucosal allergen sensitization, followed by allergen inhalation, leads to Th17-biased lung immune responses. Unlike Th17 cells generated in vitro, lung Th17 cells did not produce tumor necrosis factor-α or interleukin (IL)-22. Eosinophilia predominated in acute inflammation, while neutrophilia and IL-17 increased in chronic disease. Allergen-induced tolerance involved Foxp3-, Helios-, and glycoprotein-A repetitions predominant-expressing regulatory T cells (Treg) and IL-10/interferon-γ priming. This Treg phenotype was altered in inflamed lungs and abrogated by inhalation of IL-17. Using Th17-deficient mice with genetic disruption of gp130 in T cells, we showed that Th17 cells induce airway remodeling independent of the Th2 response. All-trans retinoic acid administration ameliorated Th17-mediated disease and increased Treg activity, while dexamethasone inhibited eosinophilia but not neutrophilia, and enhanced Th17 development in vitro. Targeting the Th17/Treg axis might therefore be therapeutic in neutrophilic and glucocorticoid-refractory asthma.


Subject(s)
Airway Remodeling/immunology , Immune Tolerance , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology , Allergens/immunology , Animals , Asthma/immunology , Asthma/pathology , Cell Differentiation/drug effects , Cell Differentiation/immunology , DNA-Binding Proteins/metabolism , Dexamethasone/pharmacology , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Interferon-gamma/biosynthesis , Interleukin-10/biosynthesis , Interleukin-17/immunology , Lung/immunology , Lung/pathology , Mice , Mice, Knockout , Permeability , Phenotype , Respiratory Mucosa/immunology , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/cytology , Th17 Cells/drug effects , Th17 Cells/metabolism , Th2 Cells/immunology , Th2 Cells/metabolism , Transcription Factors/metabolism , Tretinoin/pharmacology
13.
Mucosal Immunol ; 5(5): 524-34, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22549744

ABSTRACT

The lung is colonized by commensal bacteria, some of which are associated with asthma exacerbations. Using the intranasal house-dust mite-sensitized mouse model of allergic airway disease, we show an imbalance in novel antibacterial pathways that culminates in a reduction in neutrophil recruitment to the airspaces and leads to bacterial invasion and dissemination. The expression of TREM (Triggering Receptor Expressed on Myeloid cells)-1 that amplifies Toll-like receptor (TLR) signaling and TREM-2 that inhibits this process is reversed. Furthermore, endogenous TLR inhibitors (A20, Tollip, SOCS1, and IRAK-M) and proteins involved in receptor recycling (TRIAD3) are raised. Consequently, the production of neutrophil chemoattractants is reduced. Intranasal administration of either chemokine restores the ability to recruit neutrophils, which prevents bacterial invasion. A background of allergic airway disease therefore exacerbates bacterial infection by altering key antibacterial innate immune pathways that are amenable to therapeutic intervention.


Subject(s)
Lung/immunology , Neutrophils/immunology , Pneumococcal Infections/immunology , Respiratory Hypersensitivity/immunology , Streptococcus pneumoniae/immunology , Animals , Antigens, Dermatophagoides/immunology , Cell Movement , Cells, Cultured , Disease Models, Animal , Female , Gene Expression Regulation , Humans , Immunity, Innate , Lung/microbiology , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred BALB C , Neutrophils/microbiology , Pneumococcal Infections/complications , Pyroglyphidae/immunology , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Respiratory Hypersensitivity/complications , Signal Transduction , Toll-Like Receptors/metabolism , Triggering Receptor Expressed on Myeloid Cells-1
14.
Clin Exp Allergy ; 40(11): 1611-31, 2010 Nov.
Article in English | MEDLINE | ID: mdl-21039970

ABSTRACT

In 2009 the journal published in the region of 200 papers including reviews, editorials, opinion pieces and original papers that ran the full gamut of allergic disease. It is instructive to take stock of this output to determine patterns of interest and where the cutting edge lies. We have surveyed the field of allergic disease as seen through the pages of Clinical and Experimental Allergy (CEA) highlighting trends, emphasizing notable observations and placing discoveries in the context of other key papers published during the year. The review is divided into similar sections as the journal. In the field of Asthma and Rhinitis CEA has contributed significantly to the debate about asthma phenotypes and expressed opinions about the cause of intrinsic asthma. It has also added its halfpennyworth to the hunt for meaningful biomarkers. In Mechanisms the considerable interest in T cell subsets including Th17 and T regulatory cells continues apace and the discipline of Epidemiology continues to invoke a steady stream of papers on risk factors for asthma with investigators still trying to explain the post-second world war epidemic of allergic disease. Experimental Models continue to make important contributions to our understanding of pathogenesis of allergic disease and in the Clinical Allergy section various angles on immunotherapy are explored. New allergens continue to be described in the allergens section to make those allergen chips even more complicated. A rich and vibrant year helpfully summarized by some of our associate editors.


Subject(s)
Allergy and Immunology/trends , Hypersensitivity/immunology , Periodicals as Topic/trends , Animals , Asthma/immunology , Bibliometrics , Disease Models, Animal , Humans , Hypersensitivity/epidemiology , Hypersensitivity/therapy , Rhinitis/immunology , Risk Assessment , Risk Factors , T-Lymphocyte Subsets/immunology , Time Factors
15.
Mucosal Immunol ; 3(4): 334-44, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20505664

ABSTRACT

The absolute requirement of the pulmonary immune system is to limit the inflammatory consequences of inhaled infectious agents while maintaining tolerance to harmless aeroallergens. This tolerance is maintained by a complex network of cells and molecules interacting with lung stromal cells. However, in some individuals there is a breakdown in tolerance to particles such as pollens, animal dander, or dust, resulting in the development of allergic pathology. Emerging evidence suggests that this breakdown in tolerance is influenced by the genetic background of individuals as well as environmental considerations such as early exposure to respiratory pathogens. Further understanding of the mechanisms used by the pulmonary immune system to maintain tolerance might result in exploitation of novel avenues for therapy to treat the growing number of chronic asthmatic patients.


Subject(s)
Allergens/immunology , Desensitization, Immunologic , Hypersensitivity/immunology , Immune Tolerance , Lung/immunology , Allergens/therapeutic use , Animals , Cell Communication/immunology , Environmental Exposure , Humans , Hypersensitivity/therapy , Immunity, Mucosal , Immunomodulation , Respiratory Mucosa/immunology
16.
Allergy ; 65(9): 1126-33, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20148806

ABSTRACT

BACKGROUND: CC Chemokine receptor 4 (CCR4) is preferentially expressed on Th2 lymphocytes. CCR4-mediated inflammation may be important in the pathology of allergic rhinitis. Disruption of CCR4 - ligand interaction may abrogate allergen-induced inflammation. METHODS: Sixteen allergic rhinitics and six nonatopic individuals underwent both allergen and control (diluent) nasal challenges. Symptom scores and peak nasal inspiratory flow were recorded. Nasal biopsies were taken at 8 h post challenge. Sections were immunostained and examined by light or dual immunofluorescence microscopy for eosinophils, T-lymphocytes, CCR4(+)CD3(+) and CXCR3(+)CD3(+) cells and examined by in situ hybridization for CCR4, IL-4 and IFN-gamma mRNA(+) cells. Peripheral blood mononuclear cells were obtained from peripheral blood of nine normal donors and the CCR4(+)CD4(+) cells assessed for actin polymerization in response to the CCR4 ligand macrophage-derived chemokine (MDC/CCL22) and the influence of a CCR4 antagonist tested. RESULTS: Allergic rhinitics had increased early and late phase symptoms after allergen challenge compared to diluent; nonatopics did not respond to either challenge. Eosinophils, but not total numbers of CD3(+) T cells, were increased in rhinitics following allergen challenge. In rhinitics, there was an increase in CCR4(+)CD3(+) protein-positive cells relative to CXCR3(+)CD3(+) cells; CCR4 mRNA+ cells were increased and IL-4 increased to a greater extent than IFN-gamma. CCR4(+)CD4(+) T cells responded to MDC in vitro, and this response was inhibited by the selective CCR4 antagonist. CONCLUSION: Lymphocyte CCR4 expression is closely associated with induction of human allergen-induced late nasal responses. Blocking CCR4-ligand interaction may provide a novel therapeutic approach in allergic disease.


Subject(s)
Allergens/immunology , Hypersensitivity, Immediate/immunology , Receptors, CCR4/metabolism , Rhinitis, Allergic, Perennial/immunology , Rhinitis, Allergic, Seasonal/immunology , Th2 Cells/metabolism , Administration, Intranasal , Adult , Allergens/administration & dosage , Biopsy , Female , Humans , Hypersensitivity, Immediate/physiopathology , Inflammation/immunology , Inflammation/physiopathology , Male , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Receptors, CCR4/genetics , Rhinitis, Allergic, Perennial/physiopathology , Rhinitis, Allergic, Seasonal/physiopathology , Th2 Cells/immunology , Time Factors
17.
Bioinformatics ; 25(22): 3012-9, 2009 Nov 15.
Article in English | MEDLINE | ID: mdl-19703920

ABSTRACT

MOTIVATION: The Physiome Project was established in 1997 to develop tools to facilitate international collaboration in the physiological sciences and the sharing of biological models and experimental data. The CellML language was developed to represent and exchange mathematical models of biological processes. CellML models can be very complicated, making it difficult to interpret the underlying physical and biological concepts and relationships captured/described in the mathematical model. RESULTS: To address this issue a set of ontologies was developed to explicitly annotate the biophysical concepts represented in the CellML models. This article presents a framework that combines a visual language, together with CellML ontologies, to support the visualization of the underlying physical and biological concepts described by the mathematical model and also their relationships with the CellML model. Automated CellML model visualization assists in the interpretation of model concepts and facilitates model communication and exchange between different communities.


Subject(s)
Computational Biology/methods , Models, Theoretical , Algorithms , Databases, Factual , Models, Biological
18.
Bioinformatics ; 25(17): 2263-70, 2009 Sep 01.
Article in English | MEDLINE | ID: mdl-19564239

ABSTRACT

MOTIVATION: CellML is an implementation-independent model description language for specifying and exchanging biological processes. The focus of CellML is the representation of mathematical formulations of biological processes. The language captures the mathematical and model building constructs well, but does not lend itself to capturing the biology these models represent. RESULTS: This article describes the development of an ontological framework for annotating CellML models with biophysical concepts. We demonstrate that, by using these ontological mappings, in combination with a set of graph reduction rules, it is possible to represent the underlying biological process described in a CellML model.


Subject(s)
Biophysical Phenomena , Computational Biology/methods , Models, Biological , Software , Internet , Programming Languages
19.
Clin Exp Allergy ; 39(10): 1597-610, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19545261

ABSTRACT

BACKGROUND: Inhaled house dust mite (HDM) results in T-helper (TH) 2 type pathology in unsensitized mice, in conjunction with airway hyperreactivity and airway remodelling. However, the pulmonary cytokine and chemokine profile has not been reported. METHODS: We have performed a time course analysis of the characteristic molecular mediators and cellular influx in the bronchoalveolar lavage (BAL) and lung in order to define the pulmonary inflammatory response to inhaled HDM extract. Mice were exposed five times a week to soluble HDM extract for 3 weeks. Lung function was measured in groups of mice at intervals following the final HDM challenge. Recruitment of inflammatory cells and inflammatory mediator production was then assessed in BAL and lungs of individual mice. RESULTS: We found that Th2 cytokines were significantly increased in BAL and lung after HDM challenge from as early as 2 h post-final challenge. The levels of cytokines and chemokines correlated with the influx of eosinophils and Th2 cells to the different compartments of the lung. However, the production of key cytokines such as IL-4, IL-5 and IL-13 preceded the increase in airways resistance. CONCLUSION: Inhaled HDM challenge induces a classical Th2 inflammatory mediator profile in the BAL and lung. These data are important for studies determining the efficacy of novel treatment strategies for allergic airways disease.


Subject(s)
Antigens, Dermatophagoides/immunology , Cytokines/immunology , Inflammation Mediators/immunology , Lung/immunology , Pyroglyphidae/immunology , Th2 Cells/immunology , Animals , Antigens, Dermatophagoides/pharmacology , Cytokines/metabolism , Female , Inflammation , Inflammation Mediators/metabolism , Lung/metabolism , Mice , Th2 Cells/metabolism , Time Factors
20.
Biophys J ; 96(12): 4834-52, 2009 Jun 17.
Article in English | MEDLINE | ID: mdl-19527643

ABSTRACT

Spontaneously rhythmic pacemaker activity produced by interstitial cells of Cajal (ICC) is the result of the entrainment of unitary potential depolarizations generated at intracellular sites termed pacemaker units. In this study, we present a mathematical modeling framework that quantitatively represents the transmembrane ion flows and intracellular Ca2+ dynamics from a single ICC operating over the physiological membrane potential range. The mathematical model presented here extends our recently developed biophysically based pacemaker unit modeling framework by including mechanisms necessary for coordinating unitary potential events, such as a T-Type Ca2+ current, Vm-dependent K+ currents, and global Ca2+ diffusion. Model simulations produce spontaneously rhythmic slow wave depolarizations with an amplitude of 65 mV at a frequency of 17.4 cpm. Our model predicts that activity at the spatial scale of the pacemaker unit is fundamental for ICC slow wave generation, and Ca2+ influx from activation of the T-Type Ca2+ current is required for unitary potential entrainment. These results suggest that intracellular Ca2+ levels, particularly in the region local to the mitochondria and endoplasmic reticulum, significantly influence pacing frequency and synchronization of pacemaker unit discharge. Moreover, numerical investigations show that our ICC model is capable of qualitatively replicating a wide range of experimental observations.


Subject(s)
Biophysical Phenomena , Membrane Potentials , Animals , Biological Transport , Calcium/metabolism , Cell Membrane , Electrophysiological Phenomena , Ion Channel Gating , Models, Biological , Patch-Clamp Techniques , Pyloric Antrum/cytology
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